Neonatal respiratory distress syndrome (RDS) is a multifactorial developmental condition of the lungs that affects approximately 1% of newborns in general, up to 60% of premature newborns, and significantly contributes to neonatal morbidity and mortality. Previous studies support a role for the vascular endothelial growth factor (VEGF) pathway in susceptibility to RDS. Studies in animal models have shown that VEGF and members of its pathway stimulate vascularization and synthesis of surfactant. The VEGF protein is significantly decreased in plasma and bronchoalveolar lavage of infants who develop RDS and subsequent chronic lung disease, suggesting the VEGF pathway as a candidate for study. Evidence continues to build in favor of implicating genetics in susceptibility to RDS. This evidence includes genetic linkage studies for RDS, clustering of neonatal RDS within families, gene knock out animal models that result in RDS, as well as evidence that gender and ancestral background explain some of the disparity in risk of neonatal RDS. Inherited susceptibility to or protection from RDS could reside within any of the genes in the VEGF pathway potentially by influencing metabolism of the pulmonary surfactant and normal lung development. The goal of the proposed study is to investigate the potential association of genes within the VEGF pathway with neonatal RDS using a nested case control, candidate gene association study. The specific aims are: 1) Investigate neonatal genetic variation in genes involved in the VEGF pathway for susceptibility to or protection from RDS and 2) Investigate neonatal/maternal dyads and neonatal/maternal/paternal triads to investigate genes involved in the VEGF pathway for susceptibility to or protection from RDS. DNA samples from the Identification of Maternal and Fetal Genetic Factors in Preterm Birth (Prematurity) and Pregnancy Exposures and Preeclampsia Prevention (PEPP) studies will be utilized to accomplish this project. High throughput genotyping technology will be used for data collection and regression analyses and transmission disequilibrium testing will be used as analytical approaches. The overall impact of this study is a greater understanding of the biological underpinnings of RDS and the potential for moving the field closer to using genetic endowment to identify neonates requiring aggressive management for RDS. Empowering health care providers with this information will allow for better informed, evidence based management decisions for these neonates. PUBLIC HEALTH RELEVANCE: RDS remains a clinically significant condition of premature neonates and is the leading pulmonary cause of neonatal morbidity and mortality. Improved understanding of the genetic variation in the VEGF pathway and its relationship to susceptibility to or protection from RDS in neonates could suggest novel strategies to identify and categorize high risk infants and individual therapeutic strategies and ultimately improving outcomes for infants with RDS.